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Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function

Abstract

In monkeys rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), expression of the dopamine D3 receptor was decreased. However, levodopa-induced dyskinesia (LID), similar to the debilitating and pharmacoresistant involuntary movements elicited after long-term treatment with levodopa in patients with Parkinson disease (PD), was associated with overexpression of this receptor. Administration of a D3 receptor–selective partial agonist strongly attenuated levodopa-induced dyskinesia, but left unaffected the therapeutic effect of levodopa. In contrast, attenuation of dyskinesia by D3 receptor antagonists was accompanied by the reappearance of PD-like symptoms. These results indicated that the D3 receptor participated in both dyskinesia and the therapeutic action of levodopa, and that partial agonists may normalize D3 receptor function and correct side effects of levodopa therapy in patients with PD.

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Figure 1: Dyskinesia accompanied by D3 receptor overexpression.
Figure 2: A partial D3 receptor agonist, but not D3 receptor antagonists, reduced LID without affecting the therapeutic effects of levodopa.
Figure 3: The D3 receptor–selective antagonist ST 198.

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References

  1. Carlsson, A. A paradigm shift in brain research. Science 294, 1021–1024 (2001).

    Article  CAS  Google Scholar 

  2. Pulverenti, L. & Koob, G.F. Being partial to psychostimulant addiction therapy. Trends Pharmacol. Sci. 23, 151–153 (2002).

    Article  Google Scholar 

  3. Jenner, P. Pharmacology of dopamine agonists in the treatment of Parkinson's disease. Neurology 58 (suppl. 1), S1–S8 (2002).

    Article  CAS  Google Scholar 

  4. Hornykiewicz, O. Die topische Lokalisation und das Verhalten von Noradrenalin und Dopamin (3-Hydroxytyramin) in der Substantia nigra des normalen und Parkinson-kranken Menschen. Wien. Klin. Wochenschr. 75, 309–312 (1963).

    CAS  PubMed  Google Scholar 

  5. Bezard, E., Brotchie, J.M. & Gross, C.E. Pathophysiology of levodopa-induced dyskinesia: potential for new therapies. Nat. Rev. Neurosci. 2, 577–587 (2001).

    Article  CAS  Google Scholar 

  6. Lévesque, D. et al. A paradoxical regulation of the dopamine D3 receptor expression indicates the involvement of an anterograde factor from dopamine neurons. Proc. Natl. Acad. Sci. USA 92, 1719–1723 (1995).

    Article  Google Scholar 

  7. Guillin, O. et al. BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. Nature 411, 86–89 (2001).

    Article  CAS  Google Scholar 

  8. Bordet, R. et al. Induction of dopamine D3 receptor expression as a mechanism of behavioral sensitization to levodopa. Proc. Natl. Acad. Sci. USA 94, 3363–3367 (1997).

    Article  CAS  Google Scholar 

  9. Cotzias, G.C., Papavasiliou, P.S. & Gellene, R. Modification of Parkinsonism-chronic treatment with L-dopa. New Eng. J. Med. 280, 337–345 (1969).

    Article  CAS  Google Scholar 

  10. Burns, R.S. et al. A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc. Natl. Acad. Sci. USA 80, 4546–4550 (1983).

    Article  CAS  Google Scholar 

  11. Pearce, R.K., Jackson, M., Smith, L., Jenner, P. & Marsden, C.D. Chronic L-dopa administration induces dyskinesias in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmoset (Callithrix jacchus). Mov. Disord. 10, 731–740 (1995).

    Article  CAS  Google Scholar 

  12. Morissette, M. et al. Associative and limbic regions of monkey striatum express high levels of dopamine D3 receptors: effects of MPTP and dopamine agonist replacement therapies. Eur. J. Neurosci. 10, 2565–2573 (1998).

    Article  CAS  Google Scholar 

  13. Quik, M., Police, S., He, L., Di Monte, D.A. & Langston, J.W. Expression of D3 receptor messenger RNA and binding sites in monkey striatum and substantia nigra after nigrostriatal degeneration: effect of levodopa treatment. Neuroscience 98, 263–273 (2000).

    Article  CAS  Google Scholar 

  14. Ryoo, H.L., Pierrotti, D. & Joyce, J.N. Dopamine D3 receptor is decreased and D2 receptor is elevated in the striatum of Parkinson's disease. Mov. Disord. 13, 788–797 (1998).

    Article  CAS  Google Scholar 

  15. Hurley, M.J., Stubbs, C., Jenner, P. & Marsden, C.A. D3 receptor expression within the basal ganglia is not affected by Parkinson's disease. Neurosci. Lett. 214, 75–78 (1996).

    Article  CAS  Google Scholar 

  16. Pilla, M. et al. Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist. Nature 400, 371–375 (1999).

    Article  CAS  Google Scholar 

  17. Grondin, R., Tahar, A.H., Doan, V.D., Ladure, P. & Bedard, P.J. Noradrenoceptor antagonism with idazoxan improves L-dopa-induced dyskinesias in MPTP monkeys. Naunyn-Schmiedebergs Arch. Pharmacol. 361, 181–186 (2000).

    Article  CAS  Google Scholar 

  18. Sautel, F. et al. Nafadotride, a potent preferential dopamine D3 receptor antagonist, activates locomotion in rodents. J. Pharmacol. Exp. Ther. 275, 1239–1246 (1995).

    CAS  PubMed  Google Scholar 

  19. Levant, B., Bancroft, G.N. & Selkirk, C.M. In vivo occupancy of D2 dopamine receptors by 7-OH-DPAT. Synapse 24, 60–64 (1996).

    Article  CAS  Google Scholar 

  20. Millan, M.J. et al. S33084, a novel potent, selective, and competitive antagonist at dopamine D3-receptors: receptorial, electrophysiological and neurochemical profile compared with GR218,231 and L741,626. J. Pharmacol. Exp. Ther. 293, 1048–1062 (2000).

    CAS  PubMed  Google Scholar 

  21. Reavill, C. et al. Pharmacological actions of a novel high-affinity, and selective human dopamine D3 receptor antagonist, SB-277011-A. J. Pharmacol. Exp. Ther. 294, 1154–1165 (2000).

    CAS  PubMed  Google Scholar 

  22. Pilon, C. et al. Functional coupling of the human dopamine D3 receptor in a transfected NG 108-15 neuroblastoma-glioma hybrid cell line. Eur. J. Pharmacol. [Mol. Pharmacol. Sect.] 268, 129–139 (1994).

    Article  CAS  Google Scholar 

  23. Suzuki, M., Hurd, Y.L., Sokoloff, P., Schwartz, J.C. & Sedvall, G. D3 dopamine receptor mRNA is widely expressed in the human brain. Brain Res 779, 58–74 (1998).

    Article  CAS  Google Scholar 

  24. Boraud, T., Bezard, E., Bioulac, B. & Gross, C.E. Dopamine agonist-induced dyskinesias are correlated to both firing pattern and frequency alterations of pallidal neurones in the MPTP-treated monkey. Brain 124, 546–557 (2001).

    Article  CAS  Google Scholar 

  25. Accili, D. et al. A targeted mutation of the D3 receptor gene is associated with hyperactivity in mice. Proc. Natl. Acad. Sci. USA 93, 1945–1949 (1996).

    Article  CAS  Google Scholar 

  26. Baik, J.H. et al. Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors. Nature 377, 424–428.

  27. Gerfen, C.R. et al. D1and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 250, 1429–1432 (1990).

    Article  CAS  Google Scholar 

  28. Rascol, O. Medical treatment of levodopa-induced dyskinesia. Ann. Neurol. 47, S179–S188 (2000).

    Article  CAS  Google Scholar 

  29. Imbert, C., Bezard, E., Guitraud, S., Boraud, T. & Gross, C.E. Comparison of eight clinical rating scales used for the assessment of MPTP-induced parkinsonism in the Macaque monkey. J. Neurosci. Meth. 96, 71–76.

  30. Bezard, E. et al. Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease. J. Neurosci. 21, 6853–6861 (2001).

    Article  CAS  Google Scholar 

  31. Gurevich, E.V. et al. Mesolimbic dopamine D3 receptors and use of antipsychotics in patients with schizophrenia. Arch. Gen. Psychiatry 54, 225–232 (1997).

    Article  CAS  Google Scholar 

  32. Sokoloff, P. et al. Pharmacology of human D3 dopamine receptor expressed in a mammalian cell line: comparison with D2 receptor. Eur. J. Pharmacol. Mol. Pharmacol. Sect. 225, 331–337 (1992).

    Article  CAS  Google Scholar 

  33. Weber, B., Schlicker, E., Sokoloff, P. & Stark, H. Identification of the dopamine autoreceptor in the guinea-pig retina as D2 receptor using novel subtype-selective antagonists. Br. J. Pharmacol. 133, 1243–1248 (2001).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank C. Pilon and C. Imbert for technical assistance, and D. Guilloteau for the gift of [125I](E)-N-(3-iodoprop-2-enyl)-2β- carboxymethyl-3β-(4′-methylphenyl)-nortropane. This work was supported by grants from the Fédération pour la Recherche sur le Cerveau (to P.S. and C.G.), the European Commission (5th Framework Programme to P.S. and H.S.) and the Fondation pour la Recherche Médicale (to E.B. and C.G.).

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Correspondence to Erwan Bézard or Pierre Sokoloff.

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P.S. is named among co-inventors of international patents protecting the D3 receptor and its ligands. P.S. and L.L. are co-inventors in a patent application protecting the in vivo test used to identify a D3 receptor–selective antagonist.

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Bézard, E., Ferry, S., Mach, U. et al. Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function. Nat Med 9, 762–767 (2003). https://doi.org/10.1038/nm875

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